A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer's Disease and Related Dementias (ADRD)

Overview

Journal medRxiv

Date 2024 Aug 7

PMID 39108532

Authors

Po-Liang Cheng

Hui Wang

Beth A Dombroski

John J Farrell

Iris Horng

Tingting Chung

Giuseppe Tosto

Brian W Kunkle

William S Bush

Badri Vardarajan

Gerard D Schellenberg

Wan-Ping Lee

Affiliations

Soon will be listed here.

Abstract

We developed an imputation panel for Alzheimer's disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genes EXOC3L2 and DMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.

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